Project Summary The interplay between cellular adhesion and cellular signaling is essential for the development of all organs such as the brain, and for the functioning of systems such as the nervous systems. Brain Angiogenesis Inhibitors (BAIs/ADGRB1-4) are a poorly understood family of adhesion G-Protein Coupled Receptors that mediate cellular communication. They have essential roles in synapse formation and maturation; and are linked to numerous human diseases including neurological disorders and cancers. On the other hand, Neuroligins (NLs) are postsynaptic cell-adhesion molecules that interact with pre-synaptic Neurexins (NRXs) to mediate key functions in synaptogenesis. The PI has previously determined the high-resolution structures of BAI3, NL1 and the NL1/Nrx1 complex and performed functional studies to understand their roles in synapse function. Intriguingly, a recent study showed that BAI1 forms a receptor complex with NL1 and mediates NL1- dependent spine growth and synapse development linking these two important adhesion receptors. The ultimate goal of the research proposed in this application is to understand the molecular details of the BAI/NL interaction. We propose to obtain structural and biochemical information about the BAI/NL complex. We will then use the structural information to study the function of BAI and NL interaction in synapse formation. This research has a multi-disciplinary approach where the structural and biochemical data performed in the PI's lab will be complemented by the neurobiology studies performed in the laboratory of a close collaborator. We expect that this research will provide critical insights into the mechanistic details of BAI/NL function, helping to understand intercellular communication that is vital for brain functions.